Method of repelling animals using cyclohexyloxycyclohexylamines

ABSTRACT

Repelling animals with N-acetyl-4-cycloalkyloxycyclohexylamines of the formula: WHEREIN R1 is cycloalkyl, R2 is hydrogen or alkyl, and R3 is hydrogen or alkyl. Typical is N-acetyl-4-cyclohexyloxycyclohexylamine useful for repelling animals.

United States Patent Knowles Sept. 5, 1972 [54] METHOD OFREPELLINGANIMALS USING CYCLOHEXYLOXY- CYCLOHEXYLAMINES [72] Inventor: Richard N.Knowles, RD. 1, PO.

Box 302, Hockessin, Del. 19707 [22] Filed: Oct. 24, 1968 [21] Appl. No.:770,453

Related US. Application Data [62] Division of Ser. No. 634,417, April20, 1967.

[52] US. Cl ..424/320, 424/339 [5 1] Int. Cl. ..A0ln 9/00, AOln 17/00[58] Field of Search ..424/320, 339

[56] References Cited UNlTED STATES PATENTS 2,653,169 9/1953 Hurwitz eta1. ..260/561 Primary Examiner-Benjamin R. Padgett Attorney-Herbert W.Larson [57] ABSTRACT Repelling animals withN-acetyl-4-cycloalkyloxycyclohexylamines of the formula:

8 Claims, No Drawings METHOD OF REPELLING ANIMALS USINGCYCLOI'IEXYLOXYCYCLOHEXYLAMINES CROSS REFERENCE This application is adivisional of my copending application, Ser. No. 634,417, filed Apr. 20,1967.

BACKGROUND OF THE INVENTION The following applications relate tocompounds containing cyclohexyl ring structures and having utility asanimal repellants: application, Ser. No. 532,544, filed Mar. 1, 1966;No. 574,276, filed Aug. 18, 1966; No. 574,495, filed Aug. 18, 1966; No.574,496, filed Aug. 18, 1966; No. 574,498, filed Aug. 18, 1966; and No.574,499, filed Aug. 18, 1966.

I have now discovered additional classes of compounds containing acyclohexyl ring structure and having utility as animal repellants.

SUMMARY OF THE INVENTION I have discovered that animal repellantactivity is shown by the following compounds:

wherein R is cycloalkyl containing four through nine carbon atoms,

R is hydrogen or alkyl containing one through three carbon atoms, and Ris hydrogen or alkyl containing one through three carbon atoms.Substitutions on the cyclohexyl ring must be in the cis configuration toobtain optimum irritant effects.

Preferred because of excellent animal irritant activity at low rates ofapplication are the cis isomers of those compounds of formula (1)wherein R is cyclohexyl, and R is hydrogen.

Most preferred because of outstanding animal irritant activity at lowuse rates is the cis isomer of N-acetal-4-cyclohexyloxycycylohexylamine.

UTILITY Compounds of this invention cause potent irritation PREPARATIONThe compounds of this invention can be prepared by the catalytichydrogenation of 4-'alkoxy anilides prepared from the corresponding4-alkoxyanilines. These reactions are illustrated below. R R and R arethe same as defined in formula 1 above.

DMAC

mole of the anilide in 250 ml. glacial acetic acid.

Platinum oxide (2g.) is added, and the mixture is shaken on a ParrHydrogenation Apparatus at a hydrogen pressure ranging from 1 to 4atmospheres. When the required amount of hydrogen is absorbed, thecatalyst is filtered, and the filtrate is evaporated in vacuum leavingan oil. This oil is taken up in ether, and washed withdilute sodiumbicarbonate solution and then water. The ethereal solution is dried withmagnesium sulfate, filtered and evaporated in vacuum leaving an oil. Thepure N-acyl-4-alkoxycyclohexylamine is isolated from the oil bychromatography over silicic acid using a 3:1 mixture of chloroform andethylacetate as eluting solvent. These hydrogenation conditions causesome hydrogenolysis of the ethereal bonds.

COMPOSITIONS Compounds of this invention can be administered alone, butare generally contained in a composition with an inert diluent non-toxicto animals. The diluent selected depends on the route of administration.

Emulsifying agents can be used with the diluent and compound of formula(1) to aid in dispersion of the active ingredient. Emulsifying agentsthat could be used 'include alkylaryl polyethoxyalcohols, alkyl andalkylaryl polyether alcohols, polyoxyethylene sorbitol or sorbitan fattyesters, polyethylene glycol fatty esters, fatty alkylol amidecondenstates, amine salts of fatty alcohol sulfates plus long chainalcohols and oil soluble petroleum sulfonates.

The amount of emulsifying agent in the composition will-range from 0.1to 20 percent by weight.

Since the compounds of the present invention would generally beadministered by vapor or spray application, the compositions willcontain a liquid diluent such as water, acetone, hexane, gasoline,kerosene, other hydrocarbon oils, alcohols or other liquids generallyused in pharmaceutical preparations.

v The amount of active ingredient in the composition will vary from0.005 percent by weight to 95 percent or even higher. The diluent willgenerally constitute the major proportion of the composition and theamount of active ingredient will be less than 50 percent by weight. Theexact concentration of the active ingredient will depend on themechanism used for administration and will be easily understood by oneknowledgeable in pharmaceutical application rates.

APPLICATION A quantity of active ingredient sufficient to causeirritation to animal tissue is 500 to 10,000 micrograms per liter of airat exposure of 1 minute. It is expected that this rate applies to allanimals. Rates of over 20,000 micrograms per liter of air at exposure of1 minute kill 50 percent of the mice which are treated.

The following additional examples are provided to more particularlyexplain the invention.

EXAMPLE 1 A stirring solution of 50 grams (0.27 mole) of 4-phenoxyaniline in 200 ml. of dimethylacetamide is treated with 50 ml. ofacetic anhydride. The temperature of the solution rises to about 60 C.After having stirred for minutes, the solution is poured into 1,500 ml.of water. The dark crystals which separate are filtered and washed withwater. The crystals are recrystallized from benzene; the color islargely removed with activated charcoal during this step. The4-phenoxyacetanilide (54 grams, 88 percent of theory) melts at 129 C.

The 4-phenoxyacetanilide (35 grams; 0.15 mole) is dissolved in 250 ml.of glacial acetic acid and 2 grams of platinum oxide is added. Themixture is shaken on a Parr Hydrogenation Apparatus at a pressure of lto 4 atmospheres until 0.9 moles of hydrogen are absorbed; this requiresseveral days. The catalyst is filtered, and the filtrate is evaporatedin vacuum leaving an oil. The residual acetic acid is removed by takingthe oil up in ether and washing it several times with dilute sodiumbicarbonate solution. The ethereal solution is then dried with magnesiumsulfate, filtered and evaporated in vacuum leaving an oil.

Analysis of this oil by an F & M Model, 500 Gas Chromatograph using a 10percent Carbowax M on 60-80 mesh Diatoport T in a 2feet XAinch O.D.stainless steel column at a column temperature of 230 C., a blocktemperature of 340 C., an injection port temperature of 285 C., and ahelium flow rate of 60 cc./min. shows that about 50 percent of thismixture is N'acetylcyclohexylamine and 50 percent cis and transN-acetyl-4-cyclohexyloxycyclohexylamine.

The desired N-acetyl-4-cyclohexyloxycyclohexylamine(either as acis/trans mixture or the pure cis and trans isomers) can be isolated bychromatography over silicic acid using a 3:1 mixture of chloroform andethylacetate as eluant. The pure cis isomer melts at 86.0 to 875 C., andthe pure trans isomer melts at l42.0 to l42.5 C.

Anal. Calcd. for C ,H -,NO C, 70,3; H, 10.5; N, 5.9%. Found:

C, 70.1; H, 10.5; N, 6.2%.

The trans isomer is about half as active an irritant as the cis isomer.This cis/trans mixture can be used as an irritant without separation ofthe isomers.

Mice are treated by aerosol exposure to this cis/trans mixture ofN-acetyl-4-cyclohexyloxycyclohexylamine in the following manner: Thecompound is administered as an aerosol into a 2.8 liter chamber. Theexposure chamber consists of a 2.8 liter bell jar over a nebullizerinserted through the floor of the chamber. Mice are exposed for 5minutes to 3,000 micrograms per liter (15,000 Ct). The compound isdissolved in 1.4 ml. acetone and during a span of 20 seconds thecompound is sprayed up into the chamber. No further air is transferredinto or out of the chamber during the 5 minute exposure.

After this exposure, irritant effects are observed in all mice exposed,but not in controls exposed to 1.4 ml.

of acetone alone. Irritant effects can be described as the presence ofone or more of the following reactive signs:

a. abnormal gait,

b. depression,

c. dyspnea,

d. hunched posture, and

e. hypersensitive to touch EXAMPLES 2 7 The following compounds are madein the manner of N-acetyl-4-cyclohexyloxycyclohexylamine of Example 1 bysubstituting like molar amounts of the appropriate aniline for the4-phenoxyaniline and acid anhydride for the acetic anhydride of Example1.

2. N-Propionyl 4-cyclopentyloxycyclohexylamine.

3. N-Butanoyl-4-cyclobutyloxycyclohexylamine.

4. N-Acetyl-4-cycloheptyloxycyclohexylamine.

5 N-Methyl-N-acetyl-4-cyclobutyloxycyclohexylamine. v

6. N-Formyl-4-cyclononyloxycyclohexylamine.

7. N-Acetyl-4-cyclooctyloxycyclohexylamine.

EXAMPLE 8 A 2 percent solution ofN-acetyl-cis-4-cyclohexyloxycyclohexylamine in a 1:1 by volume mixtureof ethanol and d-ichloromethane is dispersed as an aerosol into andthrough a chamber containing rats weighing about 200 grams.

The aerosol is generated by feeding the solution of test compoundthrough a commercial paint sprayer jet at the rate of 10 ml./min., anddispersing the spray with a stream of air having a flow of 44 l./min.supplied at a pressure of 62 pounds/sq.inch. The efficiency of formingrespirable particles ranges from 10 to 40 percent. This aerosol gives aconcentration of N-acetyl-cis-4- cyclohexyloxycyclohexylamine in thechamber of 1.5 mg./liter; the mass median diameter of the particles is1.2 microns with a standard geometric deviation of 1.9. After havingbeen exposed to this aerosol for 1 minute, the rats exhibit lacrimationwhich lasts for 10 minutes. An examination of the rats 24 hours afterthe exposure reveals no adverse signs or loss in body weight.

A control run using solvent alone does not produce this effect.

I claim:

1. Method of repelling animals comprising applying to an area to beprotected from animals about 500 to 10,000 micrograms per liter of airof a compound of the formula:

I ll N-C-Rg J S R1-O V wherein R is cycloalkyl containing four throughnine carbon atoms;

R is selected from the group consisting of hydrogen and alkyl of onethrough three carbon atoms;

R is selected from the group consisting of hydrogen and alkyl of onethrough three carbon atoms.

2. Method of repelling animals according to claim 1 wherein R iscyclohexyl in the compound applied.

3. Method of repelling animals according to claim 1 wherein R ishydrogen in the compound applied.

4. Method of repelling animals according to claim 1 wherein R, iscyclohexyl and R is hydrogen in the compound applied.

5. Method of repelling animals according to claim 1 wherein R ishydrogen in the compound applied.

6. Method of repelling animals according to claim 1 wherein R is methylin the compound applied.

7. Method of repelling animals comprising applying to an area to beprotected from animals in an amount sufficient to cause irritation toanimal tissue, cis-N- acetyl-4-cyclohexyloxycyclohexylamine.

8. Method of repelling animals comprising applying to an area to beprotected from animals in an amount sufficient to cause irritation toanimal tissue, cis-N-butanoyl-4-cyclohexyloxycyclohexylamine.

9. An animal irritant composition comprising a major amount of an inertdiluent non-toxic to animals and an amount sufficient to causeirritation to animal tissue of a compound of the formula:

2. Method of repelling animals according to claim 1 wherein R1 iscyclohexyl in the compound applied.
 3. Method of repelling animalsaccording to claim 1 wherein R2 is hydrogen in the compound applied. 4.Method of repelling animals according to claim 1 wherein R1 iscyclohexyl and R2 is hydrogen in the compound applied.
 5. Method ofrepelling animals according to claim 1 wherein R3 is hydrogen in thecompound applied.
 6. Method of repelling animals according to claim 1wherein R3 is methyl in the compound applied.
 7. Method of repellinganimals comprising applying to an area to be protected from animals inan amount sufficient to cause irritation to animal tissue,cis-N-acetyl-4-cyclohexyloxycyclohexylamine.
 8. Method of repellinganimals comprising applying to an area to be protected from animals inan amount sufficient to cause irritation to animal tissue,cis-N-butanoyl-4-cyclohexyloxycyclohexylamine.
 9. An animal irritantcomposition comprising a major amount of an inert diluent non-toxic toanimals and an amount sufficient to cause irritation to animal tissue ofa compound of the formula: wherein R1 is cycloalkyl containing fourthrough nine carbon atoms; R2 is selected from the group consisting ofhydrogen and alkyl of one through three carbon atoms; R3 is selectedfrom the group consisting of hydrogen and alkyl of one through threecarbon atoms.